This application is a competing renewal of Grant 5-R01ES008442 entitled Methyl Mercury Effects on Adolescent Development. The Seychelles Child development Study (SCDS) has been testing the hypothesis that methyl mercury (MeHg) exposure from consumption of a diet high in fish is associated with adverse health outcomes. Exposure to MeHg from fish consumption is thought to impair cognition and neuro-regulation of the heart. Since 1989, we have been following a cohort of 779 subjects born to mothers who consumed an average of 12 fish-meals per week during pregnancy. The subjects are now approaching 21 years of age. The subjects have been assessed for cognitive and behavioral development. In 2006, the project was expanded with funds from a competing supplement to include measurements of autonomic heart regulation. The subjects themselves habitually consume a diet high in fish. Fish contain both MeHg and nutrients including long-chain polyunsaturated fatty acids (LCPUFA) which are beneficial to brain development and heart function. Preliminary data suggest that prenatal and postnatal exposures to combined MeHg and LCPUFA in fish may be associated with distinct patterns of results. Limited information is available on postnatal exposures however. We will examine the SCDS cohort at approximately 21 and 23 years of age to assess the net cumulative risk of exposure to postnatal MeHg and recent LCPUFA status on cognitive outcomes and cardiovascular parameters. Statistical analyses will employ innovative parametric and non-parametric modeling designed to ascertain the effects on these endpoints of co-exposures to postnatal, adjusted for prenatal MeHg exposure, and/or lifetime cumulative (prenatal and postnatal) exposure to MeHg, and recent exposure to LCPUFA to ascertain the separate risks attendant to these exposures. The Seychelles population has many similarities with that of the US and can therefore serve as a sentinel for the risks and benefits of fish consumption. The low loss to follow-up provides a unique opportunity to continue to study this very well characterized cohort and differentiate prenatal from postnatal MeHg effects as its members move from adolescence to young adult life. The findings from this study will be important as governmental agencies continue to evaluate the scientific data regarding toxic effects and nutrient benefits of a high fish diet. The study should also clarify the risks and benefits of fish consumption in relation to neurocognitive and cardiac morbidity that may not become clinically manifest until later in adulthood. PUBLIC HEALTH RELEVANCE: Human exposure to MeHg is almost exclusively from fish consumption and all fish contain some MeHg. But fish also provide other highly beneficial nutrients, such as long chain polyunsaturated fatty acids (LCPUFA) that are essential for development and function of the central nervous system (CNS) and appear to mitigate some effects of prenatal mercury exposure. Findings during the past funding period demonstrate beneficial effects of prenatal MeHg, but adverse effects of postnatal MeHg on different neurocognitive and behavioral functions, and a beneficial impact on neuro-regulation of the heart, demonstrating differential net risks or benefits for these functions that are time and organ-dependent and which therefore may require different public health risk considerations and revisions of documents, such as the National Research Council Report (2002). The proposed study makes innovative use of our well-characterized cohort to determine for the first time whether LCPUFA, that actually have a continuing influence on the CNS across the life span, interact with lifetime and recent postnatal MeHg exposure to modulate its influence on neurocognition and cardiac functions. The results should have immediate and important public health implications for agencies that advise the public about fish consumption. If LCPUFA do not interact with postnatal MeHg exposure, as they do with prenatal MeHg exposure, our findings will suggest that public health risks associated with the two exposures may be different and would have to be differentially considered.